Identification of Novel Natural Dual HDAC and Hsp90 Inhibitors for Metastatic TNBC Using e-Pharmacophore Modeling, Molecular Docking, and Molecular Dynamics Studies.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 100964009 Publication Model: Electronic Cited Medium: Internet ISSN: 1420-3049 (Electronic) Linking ISSN: 14203049 NLM ISO Abbreviation: Molecules Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, c1995-

Antineoplastic Agents*/pharmacology ; Triple Negative Breast Neoplasms*/drug therapy ; HSP90 Heat-Shock Proteins*/antagonists & inhibitors ; Histone Deacetylase Inhibitors*/pharmacology; Female ; Humans ; Ligands ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Pharmacophore

Breast cancer (BC) is one of the main types of cancer that endangers women's lives. The characteristics of triple-negative breast cancer (TNBC) include a high rate of recurrence and the capacity for metastasis; therefore, new therapies are urgently needed to combat TNBC. Dual targeting HDAC6 and Hsp90 has shown good synergistic effects in treating metastatic TNBC. The goal of this study was to find potential HDAC6 and Hsp90 dual inhibitors. Therefore, several in silico approaches have been used. An e-pharmacophore model generation based on the HDAC6-ligand complex and subsequently a pharmacophore-based virtual screening on 270,450 natural compounds from the ZINC were performed, which resulted in 12,663 compounds that corresponded to the obtained pharmacophoric hypothesis. These compounds were docked into HDAC6 and Hsp90. This resulted in the identification of three compounds with good docking scores and favorable free binding energy against the two targets. The top three compounds, namely ZINC000096116556, ZINC000020761262, and ZINC000217668954, were further subjected to ADME prediction and molecular dynamic simulations, which showed promising results in terms of pharmacokinetic properties and stability. As a result, these three compounds can be considered potential HDAC6 and Hsp90 dual inhibitors and are recommended for experimental evaluation.

Curr Cancer Drug Targets. 2020;20(4):253-270. (PMID: 31793427)
Cancer Lett. 2009 May 8;277(1):8-21. (PMID: 18824292)
Sci Rep. 2022 Aug 8;12(1):13550. (PMID: 35941273)
Biochem Biophys Rep. 2022 Mar;29:101225. (PMID: 35128086)
Curr Opin Struct Biol. 2018 Feb;48:93-102. (PMID: 29149726)
Eur J Pharmacol. 2021 Apr 5;896:173922. (PMID: 33539819)
Expert Opin Investig Drugs. 2017 Nov;26(11):1199-1206. (PMID: 28952409)
BMC Cancer. 2019 Jan 24;19(1):102. (PMID: 30678647)
Cancers (Basel). 2020 Apr 08;12(4):. (PMID: 32276534)
Eur J Med Chem. 2010 Jan;45(1):149-59. (PMID: 19853976)
Comput Biol Chem. 2019 Dec;83:107113. (PMID: 31493740)
Biochim Biophys Acta Mol Cell Res. 2019 Jun;1866(6):992-1003. (PMID: 30867138)
Sci Rep. 2021 May 26;11(1):10956. (PMID: 34040090)
Acta Pharm Sin B. 2022 Oct;12(10):3891-3904. (PMID: 36213537)
SAR QSAR Environ Res. 2022 Dec;33(12):953-968. (PMID: 36469669)
J Adv Res. 2023 Apr;46:159-171. (PMID: 35752438)
J Med Chem. 2020 Sep 24;63(18):10339-10351. (PMID: 32803970)
Int J Biol Sci. 2017 Apr 8;13(4):505-517. (PMID: 28529458)
J Chem Inf Model. 2009 Oct;49(10):2356-68. (PMID: 19761201)
Breast Care (Basel). 2015 Jul;10(3):159-66. (PMID: 26557820)
Nat Chem Biol. 2016 Sep;12(9):748-54. (PMID: 27454931)
Biochem J. 2003 Mar 15;370(Pt 3):737-49. (PMID: 12429021)
J Med Chem. 2006 Oct 19;49(21):6177-96. (PMID: 17034125)
EMBO J. 2011 Aug 16;30(20):4142-56. (PMID: 21847094)
PLoS One. 2013;8(4):e59315. (PMID: 23565147)
Oncogenesis. 2021 May 13;10(5):39. (PMID: 33986242)
Sci Rep. 2021 Jul 21;11(1):14875. (PMID: 34290315)
J Recept Signal Transduct Res. 2015;35(5):370-80. (PMID: 25404235)
Inform Med Unlocked. 2021;26:100758. (PMID: 34667827)
J Biomol Struct Dyn. 2022;40(21):10665-10676. (PMID: 34286666)
Curr Top Med Chem. 2016;16(25):2779-91. (PMID: 27072700)
Mol Cell. 2007 Jan 12;25(1):151-9. (PMID: 17218278)
Bioorg Chem. 2021 Sep;114:105081. (PMID: 34153811)
Mol Cell Biochem. 2011 Feb;348(1-2):165-71. (PMID: 21082217)
Trends Pharmacol Sci. 2014 Oct;35(10):501-9. (PMID: 25234862)
Proc Natl Acad Sci U S A. 2001 Jan 2;98(1):87-92. (PMID: 11134513)
Oncotarget. 2017 Jul 5;8(46):80109-80123. (PMID: 29113288)
RSC Adv. 2022 Aug 10;12(34):22108-22118. (PMID: 36043105)
J Comput Aided Mol Des. 2006 Oct-Nov;20(10-11):647-71. (PMID: 17124629)
PLoS One. 2015 Mar 27;10(3):e0119264. (PMID: 25816325)
Breast J. 2020 May;26(5):995-999. (PMID: 31797488)
Cancers (Basel). 2020 Jan 29;12(2):. (PMID: 32013157)
Med Chem. 2007 Mar;3(2):187-97. (PMID: 17348856)
Drug Discov Today Technol. 2010 Winter;7(4):e203-70. (PMID: 24103795)
CA Cancer J Clin. 2021 Jan;71(1):7-33. (PMID: 33433946)
Eur J Med Chem. 2021 Jan 1;209:112866. (PMID: 33039722)
Lancet Oncol. 2013 May;14(6):461-71. (PMID: 23602601)
J Enzyme Inhib Med Chem. 2018 Dec;33(1):714-721. (PMID: 29616828)
Pak J Pharm Sci. 2022 Jan;35(1(Supplementary)):313-321. (PMID: 35228193)
Front Chem. 2022 Jul 22;10:975191. (PMID: 35936081)
Drug Deliv Transl Res. 2018 Oct;8(5):1483-1507. (PMID: 29978332)
Pharmacol Res. 2020 Mar;153:104683. (PMID: 32050092)
Curr Opin Struct Biol. 2011 Dec;21(6):735-43. (PMID: 21872466)
J Enzyme Inhib Med Chem. 2019 Dec;34(1):1062-1077. (PMID: 31072216)
Eur J Med Chem. 2016 Oct 21;122:280-290. (PMID: 27376491)
Bioorg Med Chem Lett. 2021 Sep 1;47:128204. (PMID: 34139324)
Comput Math Methods Med. 2022 May 31;2022:2147763. (PMID: 35685897)
Biomed Pharmacother. 2021 Feb;134:111124. (PMID: 33434782)
Front Chem. 2020 Apr 15;8:256. (PMID: 32351936)
J Biomol Struct Dyn. 2021 Sep;39(15):5638-5656. (PMID: 32672528)
Curr Med Chem. 2022;29(9):1474-1502. (PMID: 34477503)
Daru. 2017 Jun 30;25(1):17. (PMID: 28666484)
Life Sci. 2019 Dec 15;239:117009. (PMID: 31669239)
J Biomol Struct Dyn. 2021 Nov;39(18):7274-7293. (PMID: 32873178)
Bioorg Med Chem Lett. 2020 Aug 1;30(15):127281. (PMID: 32527460)

RSP2023R119 King Saud University

Keywords: ADMET; HDAC6 and Hsp90; cancer; docking; molecular dynamics; natural products

0 (Antineoplastic Agents)
0 (Ligands)
0 (HSP90 Heat-Shock Proteins)
0 (Histone Deacetylase Inhibitors)

Date Created: 20230225 Date Completed: 20230228 Latest Revision: 20231106

20231215

PMC9965823

10.3390/molecules28041771

36838758